Multi-centre trials

Co-ordinating lnvestigator (Multi-centre trial) / Principal lnvestigator (Single centre trial)... 

In a multi-centre trial involving more than 11000 patients, supplementation of diet with fish oil reduced mortality after a myocardial infarction (ElSSl-Prevenzione Trial 1999). 

This Directive establishes specific provisions regarding the conduct of clinical trials, including multi-centre trials, on human subjects involving medicinal products as defined in Article 1 of Directive 65/65/EEC, in particular relating to the implementation of good clinical practice. This Directive does not apply to non-interventional trials. 

Having separate randomisation lists for the different centres in a multi-centre trial to ensure equal numbers of patients in the treatment groups within each centre is using centre as a stratification factor this will ensure that we do not end up with treatment being confounded with centre. 

It gives an effective way of managing multi-centre trials. 

Earlier we discussed the use of stratified randomisation in multi-centre trials and where the centres are large this is appropriate. With small centres however, for example in GP trials, this does not make sense and a stratified randomisation with region defining the strata may be more appropriate. Central randomisation would be essential to manage such a scheme. 

Table 5.1 Sample means in a multi-centre trial...

Figure 5.1 Multi-centre trial - homogeneous treatment effects...

For binary data in multi-centre trials we will have a series of 2 x 2 tables, one for each of the centres. For categorical and ordinal data with c categories, we will have a series of 2 x c tables. The CMH test in the first instance provides a single p-value for the main effect of treatment. 

The ideal situation in a multi-centre trial is to have a small number of large centres (or pre-defined pseudo-centres). This gives the necessary consistency and control yet still allows the evaluation of heterogeneity. In practice, however, we do not always end up in this situation and combining centres at the data analysis stage inevitably needs to be considered. From a statistical perspective adjusting for small centres in the analysis is problematic and leads to unreliable estimates of treatment effect so we generally have to combine. 

An adjusted (or stratified) analysis for a continuous outcome variable would be two-way ANOVA. The four strata would be handled in exactly the same way as if there were four centres in a multi-centre trial. The ANOVA approach will also... 

A key element of any meta-analysis is to look for heterogeneity across the studies. This is akin to looking for treatment-by-centre interactions in a multi-centre trial, here we are looking for treatment-by-study interactions. This is done by calculating the statistic ... 

Inhibition of human basophil degranulation by successive histamine dilutions Results of a European multi-centre trial. Inflammation Research 48 17-18. 

Smolen, J. S., Kalden, ). R., Scott, D. L., Rozman, B., Kvien.T. K., Larsen, A., Loew-Friedrich, I., Oed, C., Rosenburg, R. (1999). Efficacy and safety of Leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis a double-blind, randomised, multi-centre trial. Lancet 353, 259-266. 

A number of multi-centre trials have been carried out in the US and Europe, four of which extended over two years (Padwal et al. 2003). In... 

Dobbs SM, Dobbs RJ, Charlett A (1996) Multi-centre trials U-turns by bandwagons and the patient left by the wayside. Br J Clin Pharmacol 42 143-145... 

Mossner J, Holscher AH, Herz R, et al. A double-blind study of pantopra-zole and omeprazole in the treatment of reflux oesophagitis A multi centre trial. Aliment Pharmacol Ther 1995 9 321-326. 

Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord 1994 18 99-103. 

Despite the fact that acetylsalicylic acid has been used for many years, it is only recently that controlled trials have demonstrated its efficacy in the symptomatic treatment of rheumatoid arthritis - . The results of a 3 year multi-centre trial comparing cortisone acetate and acetylsalicylic acid, given in the lowest dosage needed to keep each patient symptom-free, indicate that the efficacy of both drugs is similar in almost all respects . The condition of the patients after 3 years was better than at the start of the trial, but radiological deterioration occurred in both groups. 

Figure 14.3 Power of a multi-centre trial as a function of the number of centres given treatment by centre interaction. (See text for explanation.)...

Geeen, K. G., W. H. W. Inman, and J. M. Thoep Multi-centre trial of a mixture of ethyl chlorophenoxyisobutyrate and androsterone (Atromid) in the United Kingdom and Ireland A preliminary report. J. Atheroscler. Res. 3, 593 (1963). 

Multi-Centre Trial Group, Controlled trial of D (-)penicillamine in severe rheumatoid arthritis. Lancet 1 275 (1973). 

A multi-centre trial of mazindol in general practice in Ireland (24 ) assessed 274 male and female obese patients and 53 investigators were involved. The assessment was an open one and double-blind techniques were not used. Reasons for patients not completing the trial are shown in Table 6. 

Table 6. Reasons for patients not completing multi-centre trial of mazindol (24 )...

Evans, E. R. and Wallace, M. G. (1975) A multi-centre trial of mazindol (Teronac) in general practice in Ireland. Curr. med. Res. Opin., 3, 132. 

---